FDA approves Novo Nordisk’s Tresiba and Ryzodeg – September 25, 2015

In long-awaited news, Novo Nordisk announced FDA approval this afternoon of the next-gen basal insulin Tresiba (insulin degludec) and premixed Ryzodeg (70/30 degludec/aspart). A US launch is expected in 1Q16. Tresiba will launch in U100 and U200 prefilled 3ml FlexTouch pens. Novo Nordisk will hold a conference call this Monday (Sep 28) at 8:00 am CEST/2:00 am ET, which is pretty much in the middle of the night in the US – of course we’ll be on that call and will send you the highlights on Monday.

The Tresiba label is posted here, headlined by inclusion of a flexible dosing claim: “Administer subcutaneously once daily at any time of day.” We see this as a very meaningful advantage for patients, and a competitive advantage relative to Sanofi’s Toujeo (per the label, Toujeo should be taken at the same time every day though it’s our impression there is some flexibility there too “in real life”). As a reminder, Tresiba has a remarkable half-life of 25 hours and a duration of action of at least 42 hours. There is no hypoglycemia advantage claim in the Tresiba label, largely expected following the 2012 advisory committee and a phase 3 program that did not widely use CGM. We think that will change in the future driven by patient advocacy if nothing else. Still, clinicians and patients could very well experience less hypoglycemia in the “real world” – indeed, Tresiba trialist Dr. Bruce Bode told us as much in our discussion following today’s news (see below). We also believe a clear advantage is most patients being able to take degludec in one dose (up to the equivalent of 160 units – with the U200, patients get the advantage of reduced volume).

Today’s approval comes six months following the Class II resubmissions in March, 31 months following the profoundly disappointing FDA complete response letter in February 2013, and nearly three years since an FDA Advisory Committee voted 8-4 in favor of approval. We imagine ultimately the CRL was a mistake by FDA and this should’ve been approved on the advice of the advisory committee, but for sure, FDA has a hard job, making sure that safety and efficacy standards are upheld. The Agency is getting by with far more work to do and relatively fewer resources, and mistakes will happen. Still, this was a rough one for patients since it delayed not only degludec but also the GLP-1/basal insulin combo Xultophy. Firewalled interim results from DEVOTE – the required CVOT for Tresiba following the CRL – enabled today’s approval. To preserve trial integrity, only a small dedicated team within Novo Nordisk has access to the interim data. Full results from DEVOTE are still expected in mid-2016 – we can’t wait to get this information. While empa CVOT data showed cardioprotection, hold on to your hats! We think it’s pretty likely some GLP-1 will also show cardioprotection. And in that case –what will the two (SGLT-2 cardioprotection plus GLP-1 cardioprotection) show together! These should be additive and possibly even synergistic, though admittedly first we need to see cardioprotection from GLP-1. A MACE benefit may well be additive.

Wasting no time, Novo Nordisk also announced today that the transformative Xultophy (Tresiba/Victoza, IDegLira) has been submitted for FDA approval. This was approved in Europe in September 2014 (sigh, again the US is SO far behind the EU) and has launched in at least Switzerland, Germany, and the UK (per the 2Q15 call). As we expressed when the Tresiba CRL came out, FDA’s request for a CVOT has dramatically delayed patient access to a gamechanging next-gen therapy. We can’t remember a therapy being so highly regarded by so many KOLs …

From a competitive perspective, Tresiba will launch in the US ~9-12 months behind the 1Q15 launch of Sanofi’s new basal insulin, Toujeo (U300 insulin glargine). Toujeo saw 2Q15 revenue of ~$14 million following its first full quarter on the market. Ultimately, we expect both to be billion-dollar products – both are meaningfully better than their current “main” products Lantus and Levemir and we’re really excited for patients and doctors. On the GLP-1/basal front, Novo Nordisk is ahead of Sanofi’s LixiLan, which will be submitted in 4Q15 in the US and 1Q16 in the EU. We think Sanofi’s COACH program is innovative and look forward to seeing what Sanofi has in mind to help patients on the adherence/engagement front.

Dr. Bruce Bode enthusiastically reacted to the approval: “This is fantastic news to patients with diabetes. Tresiba is a flat, long-acting predictable basal insulin with significant reduction in nocturnal hypoglycemia and the ability to take it anytime of the day. Ryzodeg is insulin degludec with insulin aspart in a fixed ratio (70/30) – it controls glycemic excursions post-meal, as well as fasting glucose, but with a significant decrease in overall hypoglycemia compared to analog premixed insulins. The approval of degludec allows the submission of IDegLira which is a gamechanger in the type 2 space, getting the majority of patients under a 7% A1c with minimal hypoglycemia and weight gain and GI side effects.” That says it all, folks. We think both new basal insulin products will ultimately do well and we’re excited for patients as both products are clearly meaningfully better compared to predecessor products – we think this will expand the market for basal insulin. We look forward to future products using CGM or Freestyle Libre since we think these products clearly could’ve helped differentiate the next gen basal insulins. In the meantime, we look forward to ADA and investigator initiated trials for both Tresiba and Toujeo.

Close Concerns Questions

- How will Tresiba be priced in the US?

- How will patients, clinicians, and payers compare Sanofi’s Toujeo to Tresiba? How will they compare Tresiba to Levemir and Lantus?

- Will Tresiba’s flexible dosing claim be a significant marketing advantage?

- To what extent will Tresiba show a hypoglycemia advantage in the real world?

- How will Sanofi’s LixiLan compare to Novo Nordisk’s Xultophy?

- How will the market expand for basal insulin? Clearly many patients could benefit given the perentage of patients not in good control on oral only.

Tresiba Highlights from Novo Nordisk’s 2Q15 Call

• Sales of the Tresiba (insulin degludec) franchise reached DKK 330 million (~$49 million) in 2Q15, up from DKK 271 million (~$41 million) in 1Q15. These figures include sales for Ryzodeg (insulin degludec/insulin aspart) and Xultophy in addition to standalone Tresiba. This represents a 22% sequential climb, though the magnitude of sales remains constrained by low reimbursement levels in some countries. The Tresiba franchise accounted for 10% of overall growth in the first half of 2015.
• Tresiba has now been launched in 30 countries and achieved 30% market share in Japan, and penetration remains strong in other countries where it is reimbursed at a similar level to Sanofi’s Lantus (insulin glargine).
• Novo Nordisk recently announced its decision to withdraw Tresiba from the German market (Europe’s largest) following a series of negative pricing decisions. Though not unprecedented in diabetes, it is disappointing both from patient and sales perspectives given that Tresiba had achieved a not-insignificant 8% value share of the basal insulin analog market in Germany. Sanofi will have a major advantage in Germany with the only next-gen basal insulin.
• Very surprisingly, IQWiG very recently handed down a “no additional benefit” ruling for the transformative basal insulin/GLP-1 agonist combination Xultophy (insulin degludec/liraglutide). The decision is astounding given the clear benefits across the board on glucose, weight, and hypoglycemia with Xultophy. Management frankly acknowledged that Xultophy could meet a similar fate (withdrawal) in Germany as Tresiba if the final G-BA ruling matches IQWiG’s assessment. To be honest, out of all the IQWiG decisions, this one leaves us the most incredulous. Xultophy has now been launched in Switzerland, Germany, and the UK. Management stated that market penetration of Xultophy in Switzerland measured in value of the long-acting insulin market is comparable to that of Tresiba.

-- by Adam Brown and Kelly Close